title: Structure, mechanism, and dynamics of UDP-galactopyranose mutase.
abstract: The flavoenzyme UDP-galactopyranose mutase (UGM) is a key enzyme in galactofuranose biosynthesis. The enzyme catalyzes the 6-to-5 ring contraction of UDP-galactopyranose to UDP-galactofuranose. Galactofuranose is absent in humans yet is an essential component of bacterial and fungal cell walls and a cell surface virulence factor in protozoan parasites. Thus, inhibition of galactofuranose biosynthesis is a valid strategy for developing new antimicrobials. UGM is an excellent target in this effort because the product of the UGM reaction represents the first appearance of galactofuranose in the biosynthetic pathway. The UGM reaction is redox neutral, which is atypical for flavoenzymes, motivating intense examination of the chemical mechanism and structural features that tune the flavin for its unique role in catalysis. These studies show that the flavin functions as nucleophile, forming a flavin-sugar adduct that facilitates galactose-ring opening and contraction. The 3-dimensional fold is novel and conserved among all UGMs, however the larger eukaryotic enzymes have additional secondary structure elements that lead to significant differences in quaternary structure, substrate conformation, and conformational flexibility. Here we present a comprehensive review of UGM three-dimensional structure, provide an update on recent developments in understanding the mechanism of the enzyme, and summarize computational studies of active site flexibility.
authors.affiliation: Departments of Chemistry and Biochemistry, University of Missouri, Columbia, MO, United States. Electronic address: tannerjj@missouri.edu.
authors.forename: John J
authors.initials: JJ
authors.lastname: Tanner
authors.affiliation: Departments of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, United States.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Boechi
authors.affiliation: Departments of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, United States; Howard Hughes Medical Institute, Department of Pharmacology, University of California San Diego, La Jolla, CA, United States.
authors.forename: J
authors.initials: J
authors.lastname: Andrew McCammon
authors.affiliation: Department of Biochemistry, Virginia Tech, Blacksburg, VA, United States; Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA, United States. Electronic address: psobrado@vt.edu.
authors.forename: Pablo
authors.initials: P
authors.lastname: Sobrado
mesh_terms: D000818:Animals; D001419:Bacteria / Q000737:chemistry / Q000201:enzymology; D004789:Enzyme Activation; D005415:Flavins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D019751:Intramolecular Transferases / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D011487:Protein Conformation; D013379:Substrate Specificity
chemical_list: D005415:Flavins; D019751:Intramolecular Transferases; C098051:UDP-galactopyranose mutase
keywords: Conformational changes; Flavin-dependent reaction; Galactofuranose; Neglected diseases; Non-redox reaction; Protein dynamics; Redox-switch; Tuberculosis